Hereditary transthyretin amyloidosis (hATTR amyloidosis) is a rare, progressive genetic disorder. It results from the abnormal accumulation of misfolded transthyretin (TTR) protein, which forms amyloid deposits in various tissues and organs. This systemic condition affects multiple body parts, leading to diverse symptoms and complications.
Understanding the Genetic Roots
Hereditary transthyretin amyloidosis stems from a mutation in the TTR gene. This gene instructs the body to make the TTR protein, which transports thyroid hormones and Vitamin A. A mutation causes the TTR protein to become unstable, misfold, and aggregate into amyloid fibrils that deposit in tissues.
The inheritance pattern is autosomal dominant, meaning only one copy of the mutated TTR gene is needed to develop the condition. Each child of an affected parent has a 50% chance of inheriting the mutation. Even with the same mutation, symptom onset and severity can vary widely, a phenomenon known as variable penetrance.
How it Affects the Body
One of the most common impacts of hATTR amyloidosis is on the nervous system, causing neuropathy. Peripheral neuropathy can manifest as numbness, tingling, pain, or weakness in the limbs, often starting in the feet and hands, and can also lead to conditions like carpal tunnel syndrome.
Autonomic neuropathy affects involuntary bodily functions, resulting in symptoms such as digestive issues like diarrhea or constipation, unpredictable blood pressure drops upon standing (orthostatic hypotension), and erectile dysfunction.
The heart is also frequently affected, leading to cardiomyopathy where the heart walls thicken, impairing its ability to pump blood effectively. This can result in heart failure, shortness of breath, and abnormal heart rhythms (arrhythmias).
Amyloid deposits can also affect other organs, leading to various symptoms:
- Ocular manifestations, such as vitreous opacities (clouding in the eye’s gel) and increased glaucoma risk.
- Kidney involvement, leading to renal disease, proteinuria, and potentially kidney failure.
- Gastrointestinal issues, including early satiety, nausea, and unintended weight loss due to malabsorption.
- Ligament involvement, causing conditions like spinal stenosis (narrowing of the spinal canal).
Diagnosis and Early Detection
Diagnosing hereditary transthyretin amyloidosis can be challenging due to its rarity and the wide variety of symptoms that often overlap with other conditions. Its broad range of symptoms means it can mimic other more common conditions. The diagnostic process typically begins with a high clinical suspicion, based on a patient’s symptoms and a detailed family history that might suggest a genetic predisposition. Once suspicion is raised, specific tests are employed to confirm the diagnosis.
Genetic testing is a definitive step, involving a blood test to identify a mutation in the TTR gene, which confirms the hereditary nature of the disease. In conjunction with genetic testing, a tissue biopsy is frequently performed to detect amyloid deposits. Common biopsy sites include the fat pad, nerve, heart, or kidney, and the tissue samples are typically stained with Congo red, which causes amyloid to appear apple-green under polarized light.
Imaging studies are also employed to assess organ involvement and differentiate hATTR amyloidosis from other forms of amyloidosis. Cardiac MRI and echocardiography can evaluate heart wall thickness and function, while nuclear scintigraphy, particularly with a Tc-99m pyrophosphate (PYP) scan, is highly effective in detecting TTR amyloid deposits in the heart. For evaluating neuropathy, electromyography (EMG) and nerve conduction studies measure the electrical activity of muscles and nerves to identify damage. Early diagnosis is important, as timely intervention with disease-modifying therapies can improve patient outcomes.
Current Treatment Approaches
Treatment for hereditary transthyretin amyloidosis has evolved from symptomatic management to effective disease-modifying therapies. TTR stabilizers, such as tafamidis and diflunisal, bind to the TTR protein, preventing it from misfolding and forming amyloid fibrils, thereby slowing disease progression.
Gene silencers, another approach, reduce TTR protein production. Therapies like RNA interference (RNAi) drugs (e.g., patisiran, vutrisiran) or antisense oligonucleotides (ASO) (e.g., inotersen) target the mRNA responsible for TTR creation. By interfering with this process, they lower circulating TTR protein, reducing amyloid formation and addressing the disease’s root cause.
Symptomatic management remains an important component of care, addressing specific manifestations of the disease to improve a patient’s quality of life. This can include pain management for neuropathy, diuretics to manage fluid retention associated with heart failure, or pacemakers to regulate arrhythmias.
While less common now due to the efficacy of newer therapies, organ transplantation, particularly liver transplantation, was historically a primary treatment to remove the main source of mutated TTR protein. However, the disease can still progress in other organs even after a liver transplant. Heart transplantation may be considered for individuals with severe cardiomyopathy.
Looking ahead, ongoing research is exploring even more advanced therapeutic strategies, such as gene editing technologies, which aim to correct the underlying genetic mutation responsible for hATTR amyloidosis. These emerging therapies hold promise for future, potentially curative, interventions.